1. Field of the Invention
The present invention relates to aziridinyl-epothilone analogs pharmaceutical compositions comprising aziridinyl-epothilone analogs, and methods of using the same.
2. Related Background Art
Epothilones A and B are naturally-occurring compounds that were discovered by Höfle et al. as isolated from fermentation products of the microorganism, Sorangium cellulosum (see, e.g., WO 93/10121). Höfle et al. also discovered 37 natural epothilone variants and related compounds produced by Sorangium cellulosum, including epothilones C, D, E, F and other isomers and variants. See, e.g., U.S. Pat. No. 6,624,310. While in 1993 Höfle et al reported on cytotoxic effects of Epothilones A and B, in 1995 researchers with Merck reported that epothilone B exerts microtubule-stabilizing effects similar to paclitaxel (TAXOL®) (See D. M. Bollag, “Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-like Mechanism of Action,” Cancer Research, Vol. 55 (June 1995), at pp. 2325-2333).
Various derivatives and analogs of the naturally-occurring epothilones have been discovered at Bristol-Myers Squibb Co. Examples of epothilone analogs include the aza-epothilone B analog known as ixabepilone, 21-substituted analogs of epothilone B including a 21-amino analog, 2,3-olefinic analogs, C-3 cyano analogs, cyclopropyl analogs, and heterocyclic analogs including aziridinyl-epothilone analogs. See, e.g. U.S. Pat. Nos. 6,605,599; 6,262,094; 6,399,638; 6,498,257; 6,380,395; and 6,800,653, each of which is incorporated herein by reference. Others have also reported on the discovery of other epothilone derivatives and analogs. See, e.g., PCT Pub. Nos. WO 99/65913, WO 98/25929; WO 00/99/07692; WO 99/67252; WO 00/00485; WO 00/37473; WO 01/83800; WO 99/67253, WO 99/07692, WO 00/00485, WO 00/49021, WO 00/66589, WO 03/045324, WO 04/014919, WO 04/056832, WO 03/022844; U.S. Pat. Nos. 6,441,186; 6,284,781; 6,660,758; 6,380,394; 6,242,469; 6,531,497; 6,441,186; 6,489,314; 6,589,968; 6,930,102; US Pat. Appl. Pub. Nos. US 2004/0072870 A1; US 2003/0023082 A1; US 2004/0053910 A1; US 2004/0152708 A1, all of which are incorporated by reference in their entirety.
The naturally-occurring epothilones and their analogs, like other microtubule-stabilizing agents, may be useful for treating proliferative diseases such as cancer, which typically work by killing (or arresting the growth of) tumor cells, other pathogenic cells, and foreign pathogens. Often, however, anticancer drugs attack not only tumor cells but also normal tissue, leading to undesired side effects. Additionally, anticancer drugs typically present solubility issues such that formulation and delivery of the agents can present challenges, leading to use of solubilizing agents such as CREMOPHOR®. The cytotoxicity of some anticancer drugs and/or formulation ingredients has been known to cause neuropathy or other side effects such as hypersensitivity reactions. These adverse side effects highlight the need for anticancer therapies that are selective for pathogenic cell populations and therefore result in reduced host toxicity.
However, as discussed in WO 2004/054622 A1 scientists have for many years attempted to use monoclonal antibodies (mAbs) in targeted drug therapies for delivery of chemotherapeutic agents to patients, but drawbacks have been encountered in terms of, inter alia, the cleavable moiety, the linkers, and the form of drug released in the cell. It has been reported that successful therapy of tumors with mAbs is limited by inadequate penetration of the antibody in the tumor and by the heterogeneous distribution of corresponding tumor-associated antigen in the tumor tissue. See, Klar et al., WO 05/074901 (assigned to Schering AG).
US Pat. App. Pub. No. 2005/0002942 discloses vitamin receptor binding drug delivery conjugates that are useful for targeted drug delivery. There is a need in the art for identifying anticancer agents that could be used to make conjugates such as those described in US 2005/0002942, in the interest of providing targeted drug delivery for cancer treatment.